LYNPARZA- olaparib_tablet, film coated

Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer, both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA1/2 ATM Cardiac Electrophysiology The effect of olaparib on cardiac repolarization was assessed in 119 patients following a single dose of 300 mg and in 109 patients following multiple dosing of 300 mg twice daily. No clinically relevant effect of olaparib on QT interval was observed. The area under the curve (AUC) of olaparib increases approximately proportionally following administration of single doses of 25 mg to 450 mg (0. 5 times the recommended dose) and maximal concentrations (C max The mean (CV%) olaparib C max max Absorption Following oral administration of olaparib, the median time to peak plasma concentration is 1. Effect of Food Co-administration of a high fat and high calorie meal (800-1000 kcal, 50% of the calorie content made up from fat) with olaparib slowed the rate (t max Distribution The mean (+/- standard deviation) apparent volume of distribution of olaparib is 158 +/- 136 L following a single 300 mg dose of Lynparza. The protein binding of olaparib is approximately 82% in vitro. Elimination The mean (+/- standard deviation) terminal plasma half-life of olaparib is 14. 2 hours and the apparent plasma clearance is 7. 9 L/h following a single 300 mg dose of Lynparza. Metabolism Olaparib is metabolized by cytochrome P450 (CYP) 3A in vitro. Following an oral dose of radiolabeled olaparib to female patients, unchanged olaparib accounted for 70% of the circulating radioactivity in plasma. It was extensively metabolized with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively. The majority of the metabolism is attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation. Excretion Following a single dose of radiolabeled olaparib, 86% of the dosed radioactivity was recovered within a 7-day collection period, 44% via the urine and 42% via the feces. The majority of the material was excreted as metabolites. Specific Populations Patients with Renal Impairment In a renal impairment trial, the mean AUC increased by 24% and C max Patients with Hepatic Impairment In a hepatic impairment trial, the mean AUC increased by 15% and the mean C max max Drug Interaction Studies Clinical Studies CYP3A Inhibitors: max max CYP3A Inducers max max In vitro Studies CYP Enzymes UGT Enzymes Transporters.

Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: Ovarian cancer BRCA 1. 1 BRCA 1. 1 Breast cancer BRCA 1. 1 gBRCA 1. 1 Pancreatic cancer gBRCA 1. 1 Prostate cancer 1. 1 BRCA BRCA 1. 1 Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA [see Dosage and Administration (2. 1) ] Lynparza is indicated in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: BRCA Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2. 1) Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA [see Error! Hyperlink reference not valid. ] Lynparza is indicated for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCA [ Dosage and Administration (2. 1) Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious gBRCA [see Dosage and Administration (2. 1) Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCA [see Dosage and Administration (2. 1) Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2. 1) Lynparza is indicated in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA BRCAm [see Error! Hyperlink reference not valid.

2) (2. 5) Information on FDA-approved tests for the detection of genetic mutations is available at http://www. gov/companiondiagnostics. Select patients for treatment with Lynparza based on the presence of deleterious or suspected deleterious HRR gene mutations, including BRCA mutations, or genomic instability based on the indication, biomarker, and sample type (Table 1). Table 1 Biomarker Testing for Patient Selection Where testing fails or tissue sample is unavailable/insufficient, or when germline testing is negative, consider using an alternative test, if available. Indication Biomarker Sample type Tumor Blood Plasma (ctDNA) First-line maintenance treatment of germline or somatic BRCAm BRCA1 BRCA2 X X First-line maintenance treatment of HRD-positive advanced ovarian cancer in combination with bevacizumab BRCA1 BRC X Maintenance treatment of germline or somatic BRCA BRCA1 BRCA2 X X Adjuvant treatment of gBRCA gBRCA1 , gBRCA2 X g BRCA gBRCA1 gBRCA2 X First-line maintenance treatment of germline BRCA gBRCA1 gBRCA2 X Germline or somatic HRR gene-mutated metastatic castration-resistant prostate cancer ATM BRCA1 , BRCA2 BARD1 BRIP1 CDK12 CHEK1 CHEK2 FANCL PALB2 RAD51B RAD51C RAD51D RAD54L X g BRCA2 X ATM , BRCA1 BRCA2 X BRCA BRCA1 BRCA2 X X X The recommended dosage of Lynparza is 300 mg taken orally twice daily, with or without food. If a patient misses a dose of Lynparza, instruct patient to take their next dose at its scheduled time. Instruct patients to swallow tablets whole. Do not chew, crush, dissolve, or divide tablet. First-Line Maintenance Treatment of BRCA Continue treatment until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider can derive further benefit from continuous treatment, can be treated beyond 2 years. First-Line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab Continue Lynparza treatment until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider can derive further benefit from continuous Lynparza treatment, can be treated beyond 2 years. When used with Lynparza, the recommended dose of bevacizumab is 15 mg/kg every three weeks. Bevacizumab should be given for a total of 15 months including the period given with chemotherapy and given as maintenance. Refer to the Prescribing Information for bevacizumab when used in combination with Lynparza for more information. Adjuvant Treatment of Germline BRCA Continue treatment for a total of 1 year, or until disease recurrence, or unacceptable toxicity, whichever occurs first. Patients receiving Lynparza for hormone receptor positive HER2-negative breast cancer should continue concurrent treatment with endocrine therapy as per current clinical practice guidelines. Germline or Somatic BRCA BRCA BRCA Continue treatment until disease progression or unacceptable toxicity for: Maintenance treatment of germline or somatic BRCA Germline BRCA First-line maintenance treatment of germline BRCA HRR gene-mutated metastatic castration-resistant prostate cancer. BRCA Continue treatment until disease progression or unacceptable toxicity. When used with Lynparza, the recommended dose of abiraterone is 1000 mg taken orally once daily. Abiraterone should be given in combination with prednisone or prednisolone 5 mg orally twice daily. Refer to the Prescribing Information for abiraterone for dosing information. Patients with mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. To manage adverse reactions, consider interruption of treatment or dose reduction. The recommended dose reduction is 250 mg taken twice daily. If a further dose reduction is required, then reduce to 200 mg taken twice daily. Avoid concomitant use of strong or moderate CYP3A inhibitors with Lynparza. If concomitant use cannot be avoided, reduce Lynparza dosage to: After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the Lynparza dose taken prior to initiating the CYP3A inhibitor [see Drug Interactions (7. 2) Clinical Pharmacology (12. 3) Moderate Renal Impairment In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the Lynparza dosage to 200 mg orally twice daily [see Use in Specific Populations (8. 6) Clinical Pharmacology (12.

The following adverse reactions are discussed elsewhere in the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) ] Most common adverse reactions (>=10%) in clinical trials: (6. 1) 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Unless otherwise specified, the data described in the WARNINGS AND PRECAUTIONS reflect exposure to Lynparza as a single agent in 2901 patients; 2135 patients with exposure to 300 mg twice daily tablet dose including five controlled, randomized, trials (SOLO-1, SOLO-2, OlympiAD, POLO, and PROfound) and to 400 mg twice daily capsule dose in 766 patients in other trials that were pooled to conduct safety analyses. In addition to the 2901 patients, certain subsections in the WARNINGS AND PRECAUTIONS include adverse reactions observed with exposure to Lynparza with abiraterone (n=398) in PROpel. All patients with metastatic castration resistant prostate cancer received concomitant ADT or previous bilateral orchiectomy. In the pooled safety population, 56% of patients were exposed for 6 months or longer and 28% were exposed for greater than one year in the Lynparza group. In this pooled safety population, the most common adverse reactions in >=10% of patients were nausea (60%), fatigue (55%), anemia (36%), vomiting (32%), diarrhea (24%), decreased appetite (22%), headache (16%), dysgeusia (15%), cough (15%), neutropenia (14%), dyspnea (14%), dizziness (12%), dyspepsia (12%), leukopenia (11%), and thrombocytopenia (10%). First-Line Maintenance Treatment of BRCA SOLO-1 The safety of Lynparza for the maintenance treatment of patients with BRCA-mutated advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was investigated in SOLO- 1 [see Clinical Studies (14. 1) Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 52% and dose reductions due to an adverse reaction occurred in 28%. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (23%), nausea (14%), and vomiting (10%). Discontinuation due to adverse reactions occurred in 12% of patients receiving Lynparza. The most frequent adverse reactions that led to discontinuation of Lynparza were fatigue (3. 1%), anemia (2. 3%), and nausea (2. Tables 2 and 3 summarize adverse reactions and laboratory abnormalities in SOLO-1. Table 2 Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4. Adverse Reaction Lynparza tablets n=260 Placebo n=130 All Grades (%) Grades 3 en dash 4 (%) All Grades Grades 3 en dash 4 (%) Gastrointestinal Disorders Nausea 77 1 38 0 Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal distension, abdominal discomfort, and abdominal tenderness. 45 2 35 1 Vomiting 40 0 15 1 Diarrhea Includes colitis, diarrhea, and gastroenteritis. 37 3 26 0 Constipation 28 0 19 0 Dyspepsia 17 0 12 0 Stomatitis Includes stomatitis, aphthous ulcer, and mouth ulceration. 11 0 2 0 General Disorders and Administration Site Conditions Fatigue Includes asthenia, fatigue, lethargy, and malaise. 67 4 42 2 Blood and Lymphatic System Disorders Anemia 38 21 9 2 Neutropenia Includes neutropenia and febrile neutropenia. 17 6 7 3 Leukopenia Includes leukopenia and white blood cell count decreased. 13 3 8 0 Thrombocytopenia Includes platelet count decreased and thrombocytopenia. 11 1 4 2 Infections and Infestations Upper respiratory tract 28 0 23 0 UTI Includes urosepsis, urinary tract infection, urinary tract pain, and pyuria. 13 1 7 0 Nervous System Disorders Dysgeusia 26 0 4 0 Dizziness 20 0 15 1 Metabolism and Nutrition Disorders Decreased appetite 20 0 10 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea Includes dyspnea and dyspnea exertional. 15 0 6 0 Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza were increased blood creatinine (8%), lymphopenia (6%), VTE (3%), hypersensitivity (2%), MDS/AML (1. 9%), dermatitis (1%), and increased mean cell volume (0. Table 3 Laboratory Abnormalities Reported in >=25% of Patients in SOLO-1 Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. Lynparza tablets n This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter. =260 Placebo n =130 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Decrease in hemoglobin 87 19 63 2 Increase in mean corpuscular volume 87 - 43 - Decrease in leukocytes 70 7 52 1 Decrease in lymphocytes 67 14 29 5 Decrease in absolute neutrophil count 51 9 38 6 Decrease in platelets 35 1 20 2 Increase in serum creatinine 34 0 18 0 First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab PAOLA-1 The safety of Lynparza in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer following first-line treatment containing platinum-based chemotherapy and bevacizumab was investigated in PAOLA-1 [see Clinical Studies (14. 2) Fatal adverse reactions occurred in 1 patient due to concurrent pneumonia and aplastic anemia. Serious adverse reactions occurred in 31% of patients who received Lynparza/bevacizumab. Serious adverse reactions in >5% of patients included hypertension (19%) and anemia (17%). Dose interruptions due to an adverse reaction of any grade occurred in 54% of patients receiving Lynparza/bevacizumab and dose reductions due to an adverse reaction occurred in 41% of patients who received Lynparza/bevacizumab. The most frequent adverse reactions leading to dose interruption in the Lynparza/bevacizumab arm were anemia (21%), nausea (7%), vomiting (3%), and fatigue (3%), and the most frequent adverse reactions leading to reduction in the Lynparza/bevacizumab arm were anemia (19%), nausea (7%), and fatigue (4%). Discontinuation due to adverse reactions occurred in 20% of patients receiving Lynparza/bevacizumab. Specific adverse reactions that most frequently led to discontinuation in patients treated with Lynparza/bevacizumab were anemia (4%) and nausea (3%). The most common adverse reactions (>= 10%) for patients receiving Lynparza/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), diarrhea (18%), neutropenia (18%), leukopenia (18%), urinary tract infection (15%), and headache (14%). Tables 4 and 5 summarize adverse reactions and laboratory abnormalities in PAOLA-1, respectively. Table 4 Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4. Adverse Reactions Lynparza/bevacizumab n=535 Placebo/bevacizumab Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) General Disorders and Administration Site Conditions Fatigue (including asthenia) Includes asthenia and fatigue. 5 Gastrointestinal Disorders Nausea 53 2. 7 Vomiting 22 1. 9 Blood and Lymphatic Disorders Anemia Includes anemia, anemia macrocytic, erythropenia, haematocrit decreased, haemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased. 4 Lymphopenia Includes B-lymphocyte count decreased, lymphocyte count decreased, lymphopenia, and T-lymphocyte count decreased. 1 Leukopenia Includes leukopenia and white blood cell count decreased. 5 Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza/bevacizumab were dysgeusia (8%), dyspnea (8%), stomatitis (5%), dyspepsia (4. 3%), erythema (3%), dizziness (2. 6%), hypersensitivity (1. 7%), and MDS/AML (0. Venous thromboembolism occurred more commonly in patients receiving Lynparza/bevacizumab (5%) than in those receiving placebo/bevacizumab (1. Table 5 Laboratory Abnormalities Reported in >=25% of Patients in PAOLA-1 Reported within 30 days of the last dose. Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. Lynparza/bevacizumab =535 Placebo/bevacizumab This number represents the safety population. =267 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Decrease in hemoglobin 79 13 55 0. 4 Decrease in lymphocytes 63 10 42 3. 0 Increase in serum creatinine 61 0. 4 Decrease in leukocytes 59 3. 2 Decrease in absolute neutrophil count 35 7 30 3. 7 Decrease in platelets 35 2. 4 Maintenance Treatment of BRCA SOLO-2 The safety of Lynparza for the maintenance treatment of patients with platinum sensitive g BRCA [see Clinical Studies (14. 3) Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 45% and dose reductions due to an adverse reaction occurred in 27%. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (22%), neutropenia (9%), and fatigue/asthenia (8%). Discontinuation due to an adverse reaction occurred in 11% of patients receiving Lynparza. Tables 6 and 7 summarize adverse reactions and laboratory abnormalities in SOLO-2. Table 6 Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4. Adverse Reaction Lynparza tablets n=195 Placebo n=99 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Disorders Nausea 76 3 33 0 Vomiting 37 3 19 1 Diarrhea 33 2 22 0 Stomatitis Represents grouped term consisting of abscess oral, aphthous ulcer, gingival abscess, gingival disorder, gingival pain, gingivitis, mouth ulceration, mucosal infection, mucosal inflammation, oral candidiasis, oral discomfort, oral herpes, oral infection, oral mucosal erythema, oral pain, oropharyngeal discomfort, and oropharyngeal pain. 20 1 16 0 General Disorders and Administration Site Conditions Fatigue including asthenia 66 4 39 2 Blood and Lymphatic Disorders Anemia Represents grouped term consisting of anemia, hematocrit decreased, hemoglobin decreased, iron deficiency, mean cell volume increased, and red blood cell count decreased. 44 20 9 2 Infections and Infestations Nasopharyngitis/URI/sinusitis/ rhinitis/influenza 36 0 29 0 Musculoskeletal and Connective Tissue Disorders Arthralgia/myalgia 30 0 28 0 Nervous System Disorders Dysgeusia 27 0 7 0 Headache 26 1 14 0 Metabolism and Nutrition Disorders Decreased appetite 22 0 11 0 Clinically relevant adverse reactions that occurred in <20% of patients receiving Lynparza were neutropenia (19%), cough (18%), leukopenia (16%), hypomagnesemia (14%), thrombocytopenia (14%), dizziness (13%), dyspepsia (11%), increased creatinine (11%), MDS/AML (8%), edema (8%), rash (6%), VTE (5%), and lymphopenia (1%). Table 7 Laboratory Abnormalities Reported in >=25% of Patients in SOLO-2 Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. =195 Placebo n =99 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Increase in mean corpuscular volume Represents the proportion of subjects whose mean corpuscular volume was > upper limit of normal (ULN). 89 - 52 - Decrease in hemoglobin 83 17 69 0 Decrease in leukocytes 69 5 48 1 Decrease in lymphocytes 67 11 37 1 Decrease in absolute neutrophil count 51 7 34 3 Increase in serum creatinine 44 0 29 0 Decrease in platelets 42 2 22 1 Adjuvant Treatment of germline BRCA OlympiA The safety of Lynparza as monotherapy for the adjuvant treatment of patients with gBRCA-mutated HER2-negative high risk early breast cancer was investigated in OlympiA [see Clinical Studies (14. 4) ] Dose interruptions due to an adverse reaction of any grade occurred in 31% of patients receiving Lynparza; dose reductions due to an adverse reaction occurred in 23% of patients receiving Lynparza. The most frequent adverse reactions leading to dose interruption of Lynparza were anemia (11%), neutropenia (6%), nausea (5%), leukopenia (3. 5%), fatigue (3%), and vomiting (2. 9%) and the most frequent adverse reactions leading to dose reduction of Lynparza were anemia (8%), nausea (4. 7%), neutropenia (4. 2%), fatigue (3. 3%), leukopenia (1. 8%), and vomiting (1. Discontinuation due to adverse reactions occurred in 10% of patients receiving Lynparza. The adverse reactions that most frequently led to discontinuation of Lynparza were nausea (2%), anemia (1. 8%), and fatigue (1. Tables 8 and 9 summarize the adverse reactions and laboratory abnormalities, respectively, in patients in OlympiA. Table 8 Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4. 03 Adverse Reactions Lynparza tablets n=911 Placebo n=904 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Disorders Nausea 57 0. 8 23 0 Vomiting 23 0. 7 8 0 Diarrhea 18 0. 3 Stomatitis Includes aphthous ulcer, mouth ulceration, and stomatitis. 5 0 General Disorders and Administration Site Conditions Fatigue (including asthenia) 42 1. 7 Blood and Lymphatic Disorders Anemia Includes anemia, anemia macrocytic, erythropenia, hematocrit decreased, hemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased. 3 Leukopenia Includes leukopenia and white blood cell count decreased. 3 Neutropenia Includes agranulocytosis, febrile neutropenia, granulocyte count decreased, granulocytopenia, idiopathic neutropenia, neutropenia, neutropenic infection, neutropenic sepsis, and neutrophil count decreased. 8 Nervous System Disorders Headache 20 0. 1 Dysgeusia Includes dysgeusia and taste disorder. 8 0 Dizziness 11 0. 1 Metabolism and Nutrition Disorders Decreased appetite 13 0. 2 6 0 Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza were cough (9. 2%), lymphopenia (7%), dyspepsia (6%), upper abdominal pain (4. 9%), rash (4. 9%), dyspnea (4. 2%), thrombocytopenia (4. 2%), increase in creatinine (2%), hypersensitivity (0. 9%), VTE (0. 5%), dermatitis (0. 5%), increase in mean corpuscular volume (0. 2%), and MDS/AML (0. Table 9 Laboratory Abnormalities Reported in >=25% of Patients in OlympiA Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. = 911 Placebo n =904 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Decrease in lymphocytes 77 13 59 3. 7 Increase in mean corpuscular volume Represents the proportion of subjects whose mean corpuscular volume was > ULN. 8 0 Decrease in hemoglobin 65 8 31 0. 9 Decrease in leukocytes 64 5 42 0. 7 Decrease in absolute neutrophil count 39 7 27 1. 1 Germline BRCA OlympiAD The safety of Lynparza was evaluated in g BRCA [see Clinical Studies (14. 5) ] Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 35% and dose reductions due to an adverse reaction occurred in 25%. Discontinuation due to an adverse reaction occurred in 5% of patients receiving Lynparza. Tables 10 and 11 summarize the adverse reactions and laboratory abnormalities in OlympiAD. Table 10 Adverse Reactions Graded according to NCI CTCAE v4. Adverse Reaction Lynparza tablets n=205 Chemotherapy n=91 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Disorders Nausea 58 0 35 1 Vomiting 30 0 15 1 Diarrhea 21 1 22 0 Blood and Lymphatic Disorders Anemia Represents grouped terms consisting of anemia (anemia erythropenia, hematocrit decreased, hemoglobin decreased, and red blood cell count decreased). 40 16 26 4 Neutropenia Represents grouped terms consisting of neutropenia (febrile neutropenia, granulocyte count decreased, granulocytopenia, neutropenia, neutropenic infection, neutropenic sepsis, and neutrophil count decreased). 27 9 50 26 Leukopenia Represents grouped terms consisting of leukopenia (leukopenia and white blood cell count decreased). 25 5 31 13 General Disorders and Administration Site Conditions Fatigue (including asthenia) 37 4 36 1 Infections and Infestations Respiratory tract infection Represents grouped terms consisting of bronchitis, influenza, lower respiratory tract infection, nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. 27 1 22 0 Nervous System Disorders Headache 20 1 15 2 Clinically relevant adverse reactions that occurred in <20% of patients receiving Lynparza were cough (18%), decreased appetite (16%), thrombocytopenia (11%), dysgeusia (9%), lymphopenia (8%), dyspepsia (8%), dizziness (7%), stomatitis (7%), upper abdominal pain (7%), rash (5%), increase in serum creatinine (3%), dermatitis (1%), and VTE (1%). Table 11 Laboratory Abnormalities Reported in >=25% of Patients in OlympiAD Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. = 205 Chemotherapy n = 91 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Decrease in hemoglobin 82 17 66 3 Decrease in lymphocytes 73 21 63 3 Decrease in leukocytes 71 8 70 23 Increase in mean corpuscular volume Represents the proportion of subjects whose mean corpuscular volume was > ULN. 71 - 33 - Decrease in absolute neutrophil count 46 11 65 38 Decrease in platelets 33 3 28 0 First-line Maintenance Treatment of Germline BRCA POLO The safety of Lynparza as maintenance treatment of germline BRCA [see Clinical Studies (14. 6) ] Among patients who received Lynparza, dosage interruptions due to an adverse reaction of any grade occurred in 35% and dosage reductions due to an adverse reaction occurred in 17%. The most frequent adverse reactions leading to dosage interruption or reduction in patients who received Lynparza were anemia (11%), vomiting (5%), abdominal pain (4%), asthenia (3%), and fatigue (2%). Discontinuation due to adverse reactions occurred in 6% of patients receiving Lynparza. The most frequent adverse reaction that led to discontinuation of Lynparza was fatigue (2. Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities in patients in POLO. Table 12 Adverse Reactions Graded according to NCI CTCAE, version 4. Adverse Reaction Lynparza tablets (n=91) This number represents the safety population. Placebo (n=60) All Grades (%) Grades 3 en dash 4 (%) All Grades (%) Grades 3 en dash 4 (%) General Disorders and Administration Site Conditions Fatigue Includes asthenia and fatigue. 60 5 35 2 Gastrointestinal Disorders Nausea 45 0 23 2 Abdominal pain Includes abdominal pain, abdominal pain upper, and abdominal pain lower. 34 2 37 5 Diarrhea 29 0 15 0 Constipation 23 0 10 0 Vomiting 20 1 15 2 Stomatitis Includes stomatitis and mouth ulceration. 10 0 5 0 Blood and Lymphatic System Disorders Anemia 27 11 17 3 Thrombocytopenia Includes platelets count decreased and thrombocytopenia. 14 3 7 0 Neutropenia Includes neutropenia, febrile neutropenia, and neutrophil count decreased. 12 4 8 3 Metabolism and Nutrition Disorders Decreased appetite 25 3 7 0 Musculoskeletal and Connective Tissue Disorders Back pain 19 0 17 2 Arthralgia 15 1 10 0 Skin and Subcutaneous Tissue Disorder Rash Includes rash erythematous, rash macular, and rash maculo-papular. 15 0 5 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea Includes dyspnea and dyspnea exertional. 13 0 5 2 Infections and Infestations Nasopharyngitis 12 0 3 0 Nervous System Disorders Dysgeusia 11 0 5 0 Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza were cough (9%), abdominal pain upper (7%), blood creatinine increased (7%), dizziness (7%), headache (7%), dyspepsia (5%), leukopenia (5%), VTE (3%), hypersensitivity (2%), and lymphopenia (2%). Table 13 Laboratory Abnormalities Reported in >=25% of Patients in POLO Laboratory Parameter Patients were allowed to enter POLO with hemoglobin >=9 g/dL (CTCAE Grade 2) and other laboratory values of CTCAE Grade 1. =91 Placebo n =60 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Increase in serum creatinine 99 2 85 0 Decrease in hemoglobin 86 11 65 0 Increase in mean corpuscular volume Represents the proportion of subjects whose mean corpuscular volume was > ULN. 71 - 30 - Decrease in lymphocytes 61 9 27 0 Decrease in platelets 56 2 39 0 Decrease in leukocytes 50 3 23 0 Decrease in absolute neutrophil count 25 3 10 0 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer PROfound The safety of Lynparza as monotherapy was evaluated in patients with mCRPC and HRR gene mutations who have progressed following prior treatment with enzalutamide or abiraterone in PROfound [see Clinical Studies (14. 7) ] Fatal adverse reactions occurred in 4% of patients treated with Lynparza. These included pneumonia (1. 2%), cardiopulmonary failure (0. 4%), aspiration pneumonia (0. 4%), intestinal diverticulum (0. 4%), septic shock (0. 4%), Budd-Chiari Syndrome (0. 4%), sudden death (0. 4%), and acute cardiac failure (0. Serious adverse reactions occurred in 36% of patients receiving Lynparza. The most frequent serious adverse reactions (>=2%) were anemia (9%), pneumonia (4%), pulmonary embolism (2%), fatigue/asthenia (2%), and urinary tract infection (2%). Dose interruptions due to an adverse reaction of any grade occurred in 45% of patients receiving Lynparza; dose reductions due to an adverse reaction occurred in 22% of Lynparza patients. The most frequent adverse reactions leading to dose interruption of Lynparza were anemia (25%) and thrombocytopenia (6%) and the most frequent adverse reaction leading to reduction of Lynparza was anemia (16%). Discontinuation due to adverse reactions occurred in 18% of Lynparza. The adverse reaction that most frequently led to discontinuation of Lynparza was anemia (7%). Tables 14 and 15 summarize the adverse reactions and laboratory abnormalities, respectively, in patients in PROfound. Table 14 Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4. Adverse Reactions Lynparza tablets n=256 Enzalutamide or abiraterone n=130 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Blood and lymphatic disorders Anemia Includes anemia and hemoglobin decreased. 46 21 15 5 Thrombocytopenia Includes platelet count decreased and thrombocytopenia. 12 4 3 0 Gastrointestinal disorders Nausea 41 1 19 0 Diarrhea 21 1 7 0 Vomiting 18 2 12 1 General disorders and administration site conditions Fatigue (including asthenia) 41 3 32 5 Metabolism and nutrition disorders Decreased appetite 30 1 18 1 Respiratory, thoracic, and mediastinal disorders Cough 11 0 2 0 Dyspnea 10 2 3 0 Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza were neutropenia (9%), VTE (7%), dizziness (7%), dysgeusia (7%), dyspepsia (7%), headache (6%), pneumonia (5%), stomatitis (5%), rash (4%), blood creatinine increase (4%), pneumonitis (2%), upper abdominal pain (2%), and hypersensitivity (1%). Table 15 Laboratory Abnormalities Reported in >=25% of Patients in PROfound Laboratory Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. = 256 Enzalutamide or abiraterone n =130 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Decrease in hemoglobin 98 13 73 4 Decrease in lymphocytes 62 23 34 13 Decrease in leukocytes 53 4 21 0 Decrease in absolute neutrophil count 34 3 9 0 Treatment of BRCA PROpel The safety of Lynparza in combination with abiraterone and prednisone or prednisolone for the treatment of patients in the first-line mCRPC setting was investigated in PROpel [see Clinical Studies (14. 8) Fatal adverse reactions occurred in 6% of patients, including COVID-19 (3%) and pneumonias (0. Serious adverse reactions occurred in 39% of patients. Serious adverse reactions reported in > 2% of patients included anemia (6%), COVID-19 (6%), pneumonia (4. 5%), pulmonary embolism (3. 5%), and urinary tract infection (3%). Permanent discontinuation of Lynparza due to adverse reactions occurred in 16% of patients treated in the Lynparza with abiraterone arm. The most common adverse reactions which resulted in permanent discontinuation of Lynparza were anemia (4. 3%) and pneumonia (1. Dosage interruption of Lynparza due to adverse reactions occurred in 48% of patients treated in the Lynparza with abiraterone arm. The most common (>2%) adverse reactions requiring dosage interruption of Lynparza were anemia (16%), COVID-19 (6%) fatigue (3. 5%), nausea (2. 8%), pulmonary embolism (2. 3%), and diarrhea (2. Dose reduction of Lynparza due to adverse reactions occurred in 21% of patients treated in the Lynparza with abiraterone arm. The most common (>2%) adverse reactions requiring dosage reductions of Lynparza were anemia (11%) and fatigue (2. The most common adverse reactions (>=10%) in patients who received Lynparza/abiraterone were anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), abdominal pain (13%), and dizziness (14%). Tables 16 and 17 summarize adverse reactions and laboratory abnormalities in PROpel, respectively. Table 16 Adverse Reactions (>=10%) in Patients Who Received Lynparza (with a Difference of >=5% Compared to Placebo) in PROpel Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4. Lynparza/abiraterone Placebo/abiraterone Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Blood and Lymphatic Disorders Anemia Includes anemia, anemia macrocytic, and red blood cell count decreased 48 16 18 3. 3 Lymphopenia Includes lymphocyte count decreased and lymphopenia 14 5 6 1. 8 General Disorders and Administration Site Conditions Fatigue (including asthenia) 38 2. 5 Gastrointestinal Disorders Nausea 30 0. 3 Diarrhea 19 1 10 0. 3 Abdominal pain Includes abdominal discomfort, abdominal pain, abdominal pain upper, and abdominal pain lower 13 0 7 0. 5 Metabolism and nutrition disorders Decreased appetite 16 1 7 0 Nervous System Disorders Dizziness Includes dizziness and vertigo. 3 7 0 Clinically relevant adverse reactions that occurred in <10% for patients receiving Lynparza plus abiraterone were headache (9%), VTE (8%), rash (7%), dysgeusia (6%), acute kidney injury (3%), and stomatitis (2. Table 17 Selected Laboratory Abnormalities Reported in >=20% of Patients in PROpel Laboratory Parameter Lynparza/abiraterone This number represents the safety population. Placebo/abiraterone Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Decrease in hemoglobin 97 12 81 1. 3 Decrease in lymphocytes 70 23 49 11 Decrease in platelets 23 1. 3 Decrease in absolute neutrophil count 23 5 6 0 The following adverse reactions have been identified during post-approval use of Lynparza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders Skin and subcutaneous tissue disorders.

Lactation: Advise women not to breastfeed. 2) Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12. 1) (see Data The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U. general population of major birth defects is 2-4%; and the risk for spontaneous abortion is approximately 15-20% in clinically recognized pregnancies. Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to Day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 7% of the human exposure (AUC 0-24h In an embryo-fetal development study, pregnant rats received oral doses of 0. 5 mg/kg/day olaparib during the period of organogenesis. A dose of 0. 5 mg/kg/day (with maternal systemic exposures approximately 0. 18% of human exposure (AUC 0-24h Risk Summary No data are available regarding the presence of olaparib in human milk, or on its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infants from Lynparza, advise a lactating woman not to breastfeed during treatment with Lynparza and for one month after receiving the last dose. Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8. 1) Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating treatment with Lynparza. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for 6 months following the last dose. Males Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza [see Use in Specific Populations (8. 1) Nonclinical Toxicology (13. 1) Safety and effectiveness of Lynparza have not been established in pediatric patients. Of the 2901 patients with advanced solid tumors who received Lynparza as a single agent, 680 (23%) patients were aged >=65 years, and this included 206 (7%) patients who were aged >=75 years. Thirteen (0. 4%) patients were aged >=85 years. Of the 535 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with bevacizumab (PAOLA-1), 204 (38%) patients were aged >=65 years, and this included 31 (6%) patients who were aged >=75 years. Of the 398 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with abiraterone and prednisone or prednisolone (PROpel), 268 (67%) patients were aged >=65 years, and this included 95 (24%) patients who were aged >=75 years. No overall differences in the safety or effectiveness of Lynparza were observed between these patients and younger patients. No dosage modification is recommended in patients with mild renal impairment (CLcr 51 to 80 mL/min estimated by Cockcroft-Gault). Reduce Lynparza dosage to 200 mg twice daily in patients with moderate renal impairment (CLcr 31 to 50 mL/min) [see Dosage and Administration (2. 5) [see Clinical Pharmacology (12. 3) No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C) [see Clinical Pharmacology (12.

3 Clinical studies of Lynparza with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. Strong and Moderate CYP3A Inhibitors Coadministration of CYP3A inhibitors can increase olaparib concentrations, which may increase the risk for adverse reactions [see Clinical Pharmacology (12. 3) [see Dosage and Administration (2. 4) Strong and Moderate CYP3A Inducers Concomitant use with a strong or moderate CYP3A inducer decreased olaparib exposure, which may reduce Lynparza efficacy [see Clinical Pharmacology (12.

Data
Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to Day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 7% of the human exposure (AUC 0-24h In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.18% of human exposure (AUC 0-24h
NONCLINICAL TOXICOLOGY
Carcinogenicity studies have not been conducted with olaparib. Olaparib was clastogenic in an in vitro chromosomal aberration assay in mammalian Chinese hamster ovary (CHO) cells and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of olaparib and indicates potential for genotoxicity in humans. Olaparib was not mutagenic in a bacterial reverse mutation (Ames) test. In a fertility study, female rats received oral olaparib at doses of 0.05, 0.5, and 15 mg/kg/day for at least 14 days before mating through the first week of pregnancy. There were no adverse effects on mating and fertility rates at doses up to 15 mg/kg/day (maternal systemic exposures approximately 7% of the human exposure (AUC 0-24h In a male fertility study, olaparib had no effect on mating and fertility in rats at oral doses up to 40 mg/kg/day following at least 70 days of olaparib treatment (with systemic exposures of approximately 5% of the human exposure (AUC 0-24h
CLINICAL STUDIES
The efficacy of Lynparza was evaluated in SOLO-1 (NCT01844986), a randomized (2:1), double-blind, placebo-controlled, multi-center trial in patients with BRCA A total of 391 patients were randomized, 260 to Lynparza and 131 to placebo. The median age of patients treated with Lynparza was 53 years (range: 29 to 82) and 53 years (range: 31 to 84) among patients on placebo. The ECOG performance status (PS) was 0 in 77% of patients receiving Lynparza and 80% of patients receiving placebo. Of all patients, 82% were White, 36% were enrolled in the U. or Canada, and 82% were in complete response to their most recent platinum-based regimen. The majority of patients (n=389) had germline BRCA BRCA BRCA BRCA Of the 391 patients randomized in SOLO-1, 386 were retrospectively or prospectively tested with a Myriad BRACAnalysis test and 383 patients were confirmed to have deleterious or suspected deleterious g BRCA BRCA SOLO-1 demonstrated a statistically significant improvement in investigator-assessed PFS for Lynparza compared to placebo. Results from a blinded independent review were consistent. At the time of the analysis of PFS, overall survival (OS) data were not mature (21% of patients had died). Efficacy results are presented in Table 18 and Figure 1. Table 18 Efficacy Results - SOLO-1 (Investigator Assessment) Lynparza tablets (n=260) Placebo (n=131) Progression-Free Survival Median follow-up of 41 months in both treatment arms. Number of events (%) 102 (39%) 96 (73%) Median, months NR 13. 8 Hazard ratio A value <1 favors Lynparza. Hazard ratio from a Cox proportional hazards model including response to previous platinum chemotherapy (complete response versus partial response) as a covariate. 41) p-value The p-value is derived from a stratified log-rank test. 0001 NR not reached; CI Confidence Interval. Figure 1 Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival - SOLO-1 Figure 1 PAOLA-1 (NCT02477644) was a randomized, double-blind, placebo-controlled, multi-center trial that compared the efficacy of Lynparza in combination with bevacizumab versus placebo/bevacizumab for the maintenance treatment of advanced high-grade epithelial ovarian cancer, fallopian tube or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab. Randomization was stratified by first-line treatment outcome (timing and outcome of cytoreductive surgery and response to platinum-based chemotherapy) and t BRCA registered The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST, version 1. An additional efficacy endpoint was overall survival (OS). A statistically significant difference in PFS was observed in the intent-to-treat (ITT) population. Planned exploratory analyses of PFS and OS were conducted in patients with known HRD status. The PFS hazard ratio (HR) for patients with HRD-negative tumors (277/806; 34%) was 1. 00 (95% CI: 0. 34) and the OS HR was 1. 18 (95% CI: 0. 60) indicating that the clinical benefit was primarily attributed to the results seen in the HRD-positive population. Efficacy results in patients with HRD-positive tumors are summarized in Table 19, Figure 2, and Figure 3. Among the 387 patients (48%) with HRD-positive tumors identified post-randomization using the Myriad myChoiceregistered HRD Plus tumor test the median age was 58 years in both arms (range 32-82). Ovarian cancer was the primary tumor type in 87% of patients in both arms. Ninety five percent (95%) were serous histological type. The ECOG performance score was 0 in 75% of patients and 1 in 24% of patients. All patients had received first-line platinum-based therapy and bevacizumab. First-line treatment outcomes at screening indicated that patients had no evidence of disease with complete macroscopic resection at initial debulking surgery (36%), no evidence of disease/CR with complete macroscopic resection at interval debulking surgery (29%, both arms), no evidence of disease/CR in patients who had either incomplete resection (at initial or interval debulking surgery) or no debulking surgery (16%, both arms) and patients with a partial response (19%, both arms). Sixty-two (62%) of patients in the Lynparza/bevacizumab arm and 58% of patients in placebo/bevacizumab arm had tumors with a deleterious BRCA mutation. Patients were not restricted by the surgical outcome with 67% having complete cytoreduction at initial or interval debulking surgery and 33% having residual macroscopic disease. Table 19 Efficacy Results - PAOLA-1 (HRD-positive status, Investigator Assessment) Lynparza/bevacizumab (n=255) Placebo/bevacizumab (n=132) Progression-Free Survival Results from a blinded independent review of PFS were consistent with those from investigator-assessed PFS Number of events (%) 87 (34%) 92 (70%) Median, months 37. 7 Hazard ratio The analysis was performed using an unstratified Cox proportional hazards model. 45) Overall Survival Based on final OS subgroup analysis. Number of events (%) 93 (36%) 69 (52%) Median, months 75. 3 Hazard ratiodagger (95% CI) 0. 85) CI Confidence interval. Figure 2 Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival en dash PAOLA-1 (HRD-positive status) Figure 3 Kaplan-Meier Curves of Overall Survival en dash PAOLA-1 (HRD-positive status)* * Based on final OS subgroup analysis. Figure 2 figure-3 The efficacy of Lynparza was evaluated in SOLO-2 (NCT01874353), a randomized (2:1) double-blind, placebo-controlled trial in patients with BRCA A total of 295 patients were randomized, 196 to Lynparza and 99 to placebo. The median age of patients treated with Lynparza was 56 years (range: 28 to 83) and 56 years (range: 39 to 78) among patients treated with placebo. The ECOG PS was 0 in 83% of patients receiving Lynparza and 78% of patients receiving placebo. Of all patients, 89% were White, 17% were enrolled in the U. or Canada, 47% were in complete response to their most recent platinum-based regimen, and 40% had a progression-free interval of 6-12 months since their penultimate platinum regimen. Prior bevacizumab therapy was reported for 17% of those treated with Lynparza and 20% of those receiving placebo. Approximately 44% of patients on the Lynparza arm and 37% on placebo had received three or more lines of platinum-based treatment. All (100%) patients enrolled had g BRCA All patients had a deleterious or suspected deleterious germline BRCA registered SOLO-2 demonstrated a statistically significant improvement in investigator-assessed PFS in patients randomized to Lynparza as compared with placebo. The final analysis of OS did not reach statistical significance. Efficacy results are presented in Table 20 and Figures 4 and 5. Table 20 Efficacy Results - SOLO-2 (Investigator Assessment) Lynparza tablets Placebo Progression-Free Survival 107 (55%) 80 (81%) Median, months 19. 5 Hazard ratio Hazard ratio from a Cox proportional hazards model including response to last platinum chemotherapy (complete response versus partial response) and time to disease progression in the penultimate platinum-based chemotherapy prior to enrollment (6-12 month versus >12 months) as covariates. 0001 Overall Survival Number of events (%) 116 (59) 65 (66) Median, months 51. 8 Hazard ratio 0. 00) p-value 0. 0537 Figure 4 Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival en dash SOLO-2 Figure 5 Kaplan-Meier Curves of Overall Survival en dash SOLO-2 Figure 3 Figure 4 The efficacy of Lynparza was evaluated in OlympiA (NCT02032823), a randomized (1:1), double-blind, placebo-controlled, international study in patients with gBRCAm HER2-negative high risk early breast cancer who had completed definitive local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomized to receive Lynparza tablets 300 mg orally twice daily or placebo. Treatment was continued for up to 1 year, or until disease recurrence, or unacceptable toxicity. Patients were required to have completed at least 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes or both. Prior platinum for previous cancer (e. , ovarian) or as adjuvant or neoadjuvant treatment for breast cancer was allowed. Patients with high-risk early breast cancer were defined as follows: Table 21 Early Breast Cancer Stage, Receptor Status, and Grade Scoring Requirements for Study Enrollment Total score of >=3 required for patients with hormone receptor positive breast cancer. Stage/feature Points Clinical Stage (pre-treatment) I/IIA 0 IIB/IIIA 1 IIIB/IIIC 2 Pathologic Stage (post-treatment) 0/I 0 IIA/IIB/IIIA/IIIB 1 IIIC 2 Receptor status ER positive 0 ER negative 1 Nuclear grade Nuclear grade 1-2 0 Nuclear grade 3 1 Randomization was stratified by hormone receptor status (hormone receptor positive versus triple negative), by prior neoadjuvant versus adjuvant chemotherapy, and by prior platinum use for breast cancer (yes versus no). The major efficacy outcome measure was invasive disease free survival (IDFS), defined as the time from randomization to date of first recurrence, where recurrence is defined as invasive loco-regional, distant recurrence, contralateral invasive breast cancer, new cancer or death from any cause. An additional efficacy outcome measure was OS. A total of 1836 patients were randomized, 921 to Lynparza and 915 to placebo. Demographic and baseline characteristics were well balanced between arms. The median age was 42 years. Sixty-seven percent (67%) of patients were White, 29% were Asian, and 3% were Black. Three percent (3%) of patients were Hispanic or Latino. Two patients (0. 2%) in the Lynparza arm and four patients (0. 4%) in the placebo arm were male. Sixty-one percent (61%) of patients were pre-menopausal. Eighty-nine percent (89%) of patients were ECOG performance status 0 and 11% ECOG PS 1. Eighty-two percent (82%) of patients had TNBC and 18% had hormone receptor-positive disease. Fifty percent (50%) of patients had received prior neoadjuvant and 50% received prior adjuvant chemotherapy. Ninety-four percent (94%) of patients received anthracycline and taxane chemotherapy. Twenty-six (26%) of patients overall had received prior platinum for breast cancer. Ninety percent (90%) of patients with hormone receptor positive breast cancer received concurrent endocrine therapy. Patients enrolled based on local gBRCA gBRCAm A statistically significant improvement in IDFS and OS was demonstrated in patients in the Lynparza arm compared with the placebo arm. Efficacy data for OlympiA (FAS) are presented in Table 22 and Figures 6 and 7. Table 22 Efficacy Results en dash OlympiA Lynparza tablets (N=921) Placebo (N=915) Invasive Disease Free Survival (IDFS) Data from the pre-specified interim analysis (86% of the number of events for the planned final analysis). Number of events (%) 106 (12) 178 (20) Hazard ratio (95% CI) Based on the stratified Cox''s Proportional Hazards Model. 74) p‑value (2‑sided) p-value from a stratified log-rank test. Compared with the allocated alpha of 0. 005 for IDFS and 0. 0001 3-year event-free rate, % (95% CI) Percentage are calculated using Kaplan-Meier estimates. 1) Overall Survival Data from the pre-specified second interim analysis of OS (at ~330 IDFS events). Number of events (%) 75 (8) 109 (12) Hazard ratio (95% CI) 0. 91) p‑value (2-sided) 0. 0091 3-year event-free rate, % (95% CI) 93 (90. 7, 91) CI = confidence interval. Figure 6 Kaplan-Meier Curves of IDFS en dash OlympiA Figure 7 Kaplan-Meier Curves of OS en dash OlympiA figure-6 figure-7 The efficacy of Lynparza was evaluated in OlympiAD (NCT02000622), an open-label randomized (2:1) study in patients with g BRCA A total of 302 patients were randomized, 205 to Lynparza and 97 to chemotherapy. Among the 205 patients treated with Lynparza, the median age was 44 years (range: 22 to 76), 65% were White, 4% were males and all the patients had an ECOG PS of 0 or 1. Approximately 50% of patients had triple-negative tumors and 50% had estrogen receptor and/or progesterone receptor positive tumors and the proportions were balanced across treatment arms. Patients in each treatment arm had received a median of 1 prior chemotherapy regimen for metastatic disease; approximately 30% had not received a prior chemotherapy regimen for metastatic breast cancer. Twenty-one percent of patients in the Lynparza arm and 14% in the chemotherapy arm had received platinum therapy for metastatic disease. Seven percent of patients in each treatment arm had received platinum therapy for localized disease. Of the 302 patients randomized onto OlympiAD, 299 were tested with the BRACAnalysis CDx registered BRCA A statistically significant improvement in PFS was demonstrated for the Lynparza arm compared to the chemotherapy arm. Efficacy data for OlympiAD are displayed in Table 23 and Figure 8. Consistent results were observed across patient subgroups defined by study stratification factors. An exploratory analysis of investigator-assessed PFS was consistent with the BICR-assessed PFS results. Table 23 Efficacy Results - OlympiAD (BICR-assessed) Lynparza tablets (n=205) Chemotherapy (n=97) Progression-Free Survival Number of events (%) 163 (80%) 71 (73%) Median, months 7. 2 Hazard ratio (95% CI) Hazard ratio is derived from a stratified log-rank test, stratified by ER, PgR negative versus ER and or PgR positive and prior chemotherapy (yes versus no). 80) p-value For PFS, p-value (2-sided) was compared to 0. 0009 Patients with Measurable Disease n=167 n=66 Objective Response Rate (95% CI) Response based on confirmed responses. The confirmed complete response rate was 7. 8% for Lynparza compared to 1. 5% for chemotherapy arm. 52% (44, 60) 23% (13, 35) Overall Survival Number of events (%) 130 (63%) 62 (64%) Median, months 19. 1 Hazard ratio (95% CI) 0. 23) Figure 8 Kaplan-Meier Curves of Progression-Free Survival - OlympiAD figure-8 The efficacy of Lynparza was evaluated in POLO (NCT02184195), a randomized (3:2), double-blind placebo-controlled, multi-center trial. Patients were required to have metastatic pancreatic adenocarcinoma with a deleterious or suspected deleterious germline BRCA BRCA A total of 154 patients were randomized, 92 to Lynparza and 62 to placebo. The median age was 57 years (range 36 to 84); 54% were male; 92% were White, 4% were Asian, and 3% were Black; baseline ECOG PS was 0 (67%) or 1 (31%). The median time from initiation of first-line platinum-based chemotherapy to randomization was 5. 8 months (range 3. Seventy-five percent (75%) of patients received FOLFIRINOX with a median of 9 cycles (range 4-61), 8% received FOLFOX or XELOX, 4% received GEMOX, and 3% received gemcitabine plus cisplatin; 49% achieved a complete or partial response to platinum-based chemotherapy. All patients had a deleterious or suspected deleterious germline BRCA Analysis registered registered BRCA BRCA1 BRCA2 BRCA1 BRCA2 POLO demonstrated a statistically significant improvement in BICR-assessed PFS in patients randomized to Lynparza as compared with placebo. Efficacy results of POLO are provided in Table 24 and Figure 9. Table 24 Efficacy Results - POLO (BICR-assessed) Lynparza tablets (n=92) Placebo (n=62) Progression-Free Survival Number of events (%) Number of events: Progression - Lynparza 55, placebo 44; death before BICR-documented progression - Lynparza 5, placebo 0. 60 (65) 44 (71) Median, months (95% CI) 7. 9) Hazard ratio Hazard ratio, 95% CI, and p-value calculated from a log-rank test. A hazard ratio <1 favors Lynparza. 81) p-value 0. 0035 Overall Survival Number of events (%) 61 (66) 47 (76) Median, months (95% CI) 19. 1) Hazard ratiodagger (95% CI) 0. 22) p-value 0. 3487 Patients with Measurable Disease n=78 n=52 Objective Response Rate (95% CI) 23% (14, 34) 12% (4, 23) Complete response (%) 2 (2. 6) 0 Partial response (%) 16 (21) 6 (12) Duration of Response (DOR) Median time in months (95% CI) 25 (15, NC) 4 (2, NC) NC Not calculable. Figure 9 Kaplan-Meier Curves of BICR-Assessed Progression-Free Survival en dash POLO figure-9 The efficacy of Lynparza was evaluated in PROfound (NCT02987543), randomized, open-label, multi-center trial that evaluated the efficacy of Lynparza 300 mg twice daily versus a comparator arm of investigator’s choice of enzalutamide or abiraterone acetate in men with metastatic castration-resistant prostate cancer (mCRPC). All patients received a GnRH analog or had prior bilateral orchiectomy. Patients needed to have progressed on prior enzalutamide or abiraterone for the treatment of metastatic prostate cancer and/or CRPC and have a tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway. Patients were divided into two cohorts based on HRR gene mutation status. Patients with mutations in either BRCA1 BRCA2 ATM BARD1 BRIP1 CDK12 CHEK1 CHEK2 FANCL PALB2 PPP2R2A RAD51B RAD51C RAD51D RAD54L BRCA1 BRCA2 ATM PPP2R2A registered Determination of deleterious or suspected deleterious somatic or germline HRR mutation status in line with the FDA-approved mutation classification and testing criteria for the Foundation Medicine F1CDx tissue-based assay and assessment of the germline- BRCA FANCL RAD51C Table 25 Frequency of Patients with HRR Mutations Enrolled in PROfound HRR Mutation Cohort A N=245 n (%) Cohort B Three patients with single BRCA2 ATM BRCA2+CDK12 N=142 n (%) Single mutation 224 (91) 135 (95) BRCA2 127 (52) 1 (<1) ATM 84 (34) 2 (1) BRCA1 13 (5) 0 CDK12 0 89 (63) CHEK2 0 12 (8) PPP2R2A Lynparza is not indicated for patients with PPP2R2A mutations. 0 10 (7) RAD51B 0 5 (4) RAD54L 0 5 (4) PALB2 0 4 (3) BRIP1 0 3 (2) CHEK1 0 2 (1) BARD1 0 1 (<1) RAD51D 0 1 (<1) Co-occurring mutation Patients with co-occurring mutations (BRCA1, BRCA2, or ATM plus a Cohort B gene) were assigned to Cohort A. 21 (9) 7 (5) In Cohort A+B, the median age was 69 years (range: 47 to 91 years) in both arms; 69% were White, 29% were Asian, and 1% were Black. The ECOG performance score was 0 or 1 in most patients (95%) in both arms. In patients treated with Lynparza, the proportion of patients with RECIST 1. 1 measurable disease at baseline was 58%, including 17% with lung and 10% with liver metastases, respectively. At randomization, 66% of patients had received prior taxane chemotherapy, 40% had received enzalutamide, 38% had received abiraterone acetate, and 20% had received both enzalutamide and abiraterone acetate. Patient characteristics were well-balanced between arms. The major efficacy outcome of the study was radiological progression-free survival (rPFS) (Cohort A) as determined by BICR using RECIST version 1. 1 and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) (bone) criteria. Additional efficacy outcomes included confirmed objective response rate (ORR) (Cohort A), rPFS (combined Cohorts A+B) as assessed by BICR, and overall survival (OS) (Cohort A). PROfound demonstrated a statistically significant improvement in BICR-assessed rPFS for Lynparza compared to investigator’s choice of enzalutamide or abiraterone acetate in Cohort A and Cohort A+B. In an exploratory analysis for patients in Cohort B, the median rPFS was 4. 8 months for Lynparza vs 3. 3 months for comparator with a HR of 0. 88 (95% CI 0. The major efficacy outcome was supported by a statistically significant improvement in ORR by BICR for patients with measurable disease at baseline in Cohort A. In Cohort B, ORR by BICR was 3. 7% (95% CI 0. 7) in Lynparza treated patients and 8. 3% (95% CI 1. 0) in patients treated with enzalutamide or abiraterone acetate. The final analysis of overall survival (OS) demonstrated a statistically significant improvement in OS in patients randomized to Lynparza compared to patients in the enzalutamide or abiraterone acetate arm in Cohort A. Efficacy results of PROfound are provided in Tables 26 and 27 and Figures 10 and 11. Table 26 Efficacy Results - PROfound (BICR-assessed) Cohort A Cohort A+B Although 10 patients with PPP2R2A mutation were included in all analyses of Cohort A+B, Lynparza is not indicated for this population due to unfavorable risk-benefit. Lynparza tablets Enzalutamide or Abiraterone acetate Lynparza tablets Enzalutamide or Abiraterone acetate Radiological Progression-Free Survival (rPFS) Number of events (%) 106 (65) 68 (82) 180 (70) 99 (76) Median (95% CI), in months 7. 7) Hazard ratio (95% CI) The HR and CI were calculated using a Cox proportional hazards model adjusted for prior taxane use and measurable disease. An HR <1 favors Lynparza 300 mg taken orally twice daily. 63) p-value The analysis was performed using the log-rank test stratified by prior taxane use and measurable disease. 0001 Confirmed ORR Patients with measurable disease at baseline n=84 n=43 - - ORR, n (%) 28 (33) 1 (2) - - (95% CI) (23, 45) (0, 12) - - p-value <0. 0001 - Overall Survival n=162 n=83 - - Number of events (%) 91 (56) 57 (69) - - Median (95% CI), in months 19. 8) - - Hazard ratio (95% CI) 0. 97) - p-value 0. 0175 - CI Confidence interval Figure 10 Kaplan-Meier Curves of BICR-Assessed rPFS en dash PROfound en dash Cohort A Consistent results were observed in exploratory analyses of rPFS for patients who received or did not receive prior taxane therapy and for those with germline- BRCA BRCA Figure 11 Kaplan-Meier Curves of Overall Survival en dash PROfound en dash Cohort A Response data by HRR mutations for patients in the Lynparza arm are presented in Table 27. In the comparator arm of Cohorts A and B, a total of three patients achieved a partial response, including one patient with an ATM PALB2 PPP2R2A CDK12 PALB2 Table 27 Response Rate and Duration of Response by HRR Mutation in Patients with Measurable Disease at Baseline on the Lynparza Arm en dash PROfound (BICR-assessed) HRR mutation No patients with FANCL RAD51C PPP2R2A PPP2R2A Patients (N=138) Confirmed ORR In patients with a single BRCA2 mutation the median duration of response in the Lynparza arm (n=24) was 5. 6 months (95% C. In the 3 responders with a single ATM mutation in the Lynparza arm, the duration of response ranged from 5. In the 2 responders with a single CDK12 mutation in the Lynparza arm, the duration of response was 3. + denotes ongoing response. n (%) 95% CI Single mutation BRCA2 43 24 (56) (40, 71) ATM 30 3 (10) (2, 27) CDK12 34 2 (6) (1, 20) BRCA1 6 SD, PD (4), NE NA CHEK2 4 SD (2), PD (2) NA BRIP1 2 SD, PD NA PALB2 2 SD, PD NA CHEK1 1 PD NA RAD51B 1 SD NA RAD51D 1 PD NA RAD54L 1 SD NA Co-occurring mutations BRCA2/CDK12 2 PR, SD NA BRCA2/ATM 2 SD, SD NA BRCA2/BARD1 1 PD NA BRCA2/CHEK2 1 SD NA CDK12/CHEK1 1 SD NA CDK12/PALB2 1 PD NA BRCA2/CDK12/CHEK2 1 PD NA BRCA2/CHEK2/RAD51D 1 SD NA PR Partial response; SD Stable disease; PD Progressive disease; NE Not evaluable; NA Not applicable due to small numbers or lack of response. figure_10 Figure 11 The efficacy of Lynparza in the treatment of patients with mCRPC was investigated in PROpel (NCT03732820), a randomized, double-blind, placebo-controlled, multi-center study that compared the efficacy of Lynparza in combination with abiraterone with placebo plus abiraterone for patients with mCRPC. Patients (n=796) were randomized (1:1) to receive Lynparza tablets 300 mg orally twice daily in combination with abiraterone 1000 mg daily (n=399) compared with placebo plus abiraterone (n=397). All patients received either prednisone or prednisolone 5 mg twice daily, and a GnRH analog or prior bilateral orchiectomy. Patients with prior treatment with abiraterone were excluded. Prior docetaxel for localized or metastatic hormone-sensitive prostate cancer (mHSPC) was allowed. Randomization was stratified by metastases (bone only, visceral, or other) and docetaxel treatment at mHSPC stage (yes or no). Lynparza treatment was continued until objective radiological disease progression determined by investigator or unacceptable toxicity. BRCA BRCA BRCA The major efficacy outcome measure was investigator-assessed rPFS evaluated according to RECIST, version 1. 1 and Prostate Cancer Working Group (PCWG3) (bone) criteria. Overall survival (OS) was an additional efficacy outcome measure. Of the 796 patients tested, 85 (11%) had BRCA A statistically significant improvement in rPFS for Lynparza/abiraterone compared to placebo/abiraterone was observed in the intention to treat (ITT) population. In an exploratory analysis in the subgroup of 711 patients without an identified BRCA BRCA Results of an exploratory analysis in the subgroup of 85 patients on PROpel with BRCA Results from the BICR assessment were consistent with the investigator-assessed rPFS results. Table 28 Efficacy Results en dash PROpel (Patients with BRCAm) Lynparza/abiraterone N = 47 Placebo/abiraterone N = 38 Radiological Progression-Free Survival (rPFS) Investigator-assessed. Events, n (%) 14 (30) 28 (74) Median (95% CI), months NR (NR, NR) 8 (6, 15) Hazard ratio (95% CI) Calculated using an unstratified univariable Cox proportional hazards model. 45) Overall Survival (OS) Events, n (%) 13 (28) 25 (66) Median (95% CI), months NR (NR, NR) 23 (18, 34) Hazard ratio (95% CI) 0. 59) NR: Not reached. Figure 12 Kaplan-Meier Curves of rPFS en dash PROpel (Patients with BRCA Figure 13 Kaplan-Meier Curves of OS en dash PROpel (Patients with BRCA figure-12 figure-13.

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